The goal of this proposal is to biochemically and genetically analyze a variant in the mouse that has elevated levels of high density lipoprotein (HDL) and is resistant to diet-induced atherosclerosis. This variant is particularly relevant to human heart disease since epidemiological studies have shown an association of high levels of HDL with reduced risk of heart disease. Since the mechanism of the protective role of HDL in heart disease is not understood, an analysis of the mouse variant may provide useful insights into the participation of HDL in heart disease. Mice of several common inbred strains fed an atherogenic diet show either of two distinct responses. In one phenotype, mice develop lesions in the aortic wall and have a greatly reduced HDL band on agarose gels. In the second phenotype mice fail to develop lesions in the aortic wall and continue to express HDL at the same high level. This latter phenotype corresponds to the human data showing a positive correlation between resistance to heart disease and high HDL levels. Data from 29 recombinant inbred lines indicate that the phenotypes of resistance to atherosclerosis and the high HDL band intensities cosegregate indicating that the genetic determinants of these phenotypes are either due to the same genetic factors or closely linked. Further analysis of this system has shown that the difference in atherosclerosis susceptibility is due to two separate genes, one of which to map in a cluster of genes determining HDL structure. We plan experiments to confirm the position of the first gene, to map the second gene and to determine the dominance relationships. Additional analysis is directed at determining the molecular basis for the phenotype difference in HDL levels and the mechanisms by which high levels of HDL protect against the formation of atherosclerotic lesions. In the course of this work we expect to further develop the mouse as a model experimental system for atherosclerosis research by developing a better diet; by determining a better method of quantitatively scoring lesions; and by following the progression of lesions over time. These latter experiments will facilitate the use of the mouse for atherosclerosis research by other investigators and allow the eventual analysis of other genes involved in atherosclerosis susceptibility.